Evidence implicating impaired mitochondrial function and generation of excessive reactive oxygen species (ROS) in Parkinson's disease (PD) neurodegeneration is substantial. This evidence is based on the identification of rare PD-associated mutations in genes that affect mitochondrial function such as the putative kinase 1 (PINK1), Parkin and DJ-1. Moreover, postmortem analysis revealed a reduction in mitochondrial complex I activity, and increased lipid, protein, and DNA oxidation in parkinsonian patients brains. Additionally, clinical symptoms that arise on exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a complex I inhibitor, are similar to sporadic PD. Neurons show limited glycolytic potential and are highly dependent upon mitochondrial respiration to support energy-demanding functions. However, the maintenance of the energetic levels by mitochondria implicates higher production of ROS. To maintain a proper redox balance, brain is endowed with an endogenous antioxidant defense mechanism. Nuclear factor E2-related factor 2 (Nrf2) is the master regulator of redox homeostasis, and regulates the expression of genes that share in common a cis-acting enhancer sequence termed Antioxidant Response Element (ARE), and constitute the so-called Phase II antioxidant response. High amounts of antioxidants are needed to achieve protective effects in PD, as most exogenous antioxidants do not efficiently cross the blood–brain barrier. Furthermore, administration of antioxidants is limited owing to their toxicity at high doses. This emphasizes the need for alternative strategies, and a promising candidate to limit ROS-mediated damage is the activation of endogenous antioxidant phase II enzymes. In addition, to up-regulation of the ROS scavenging system one approach toward protection that has recently take center stage in PD research, is the selective degradation of mitochondria by autophagy: mitophagy. In PD, Parkin is a possible link between mitochondrial dysfunction and mitophagy. Parkin is recruited to mitochondria via PINK1 on membrane depolarization, and regulates the clearance of dysfunctional mitochondria by mitophagy. Some recent evidences have shown that reduced autophagy worsens neurodegenerative disease phenotypes, while augmented autophagy provides benefit. Indeed, pharmacological upregulation of autophagy by resveratrol, a sirtuin 1 (SIRT1) activator, is protective in models of neuronal degeneration, suggesting that induction of basal autophagy/mitophagy could be achieved by augmentation of SIRT1 activity. Interestingly, in the presence of resveratrol AMP-activated protein kinase (AMPK) activates SIRT1 in order to promote autophagy. However, the involvement of SIRT1 and AMPK on mitophagy in PD is still unknown. Tauroursodeoxycholic acid (TUDCA) is neuroprotective in several models of neurodegenerative diseases, including Huntington's disease and Alzheirmer's disease. Recently, we showed that TUDCA protects against MPTP-induced degeneration, however the exact mechanisms underlying the neuroprotective effect of TUDCA in PD are still unidentified. In other experimental paradigms TUDCA increases the apoptotic threshold through its ability to prevent mitochondrial swelling and depolarization, and subsequent inhibition of ROS production. In this project, using the MPTP mice model of PD, we will evaluate the ability of TUDCA to rescue complex I and improve mitochondrial activity. Moreover, we will also investigate if TUDCA modulates the expression of phase II enzymes, through activation of the Nrf2 pathway. Finally, we will investigate the involvement of mitophagy as a mechanism underlying the neuroprotective effect of TUDCA in models of both sporadic and familial PD. Within this objective the recruitment of Parkin to dysfunctional mitochondria, and activation of AMPK and SIRT1 will be addressed. This project aims the identification of the mechanisms involved on TUDCA neuroprotection in PD, in order to validate its application as a therapeutic agent. In addition, TUDCA is an endogenous molecule, orally bioavailable, that crosses the blood–brain barrier, and has no associated secondary effects, which is particularly important over long-term use in a chronic disease such as PD.

• Project/scholarship ID

  124452

• Reference

  PTDC/NEU-NMC/0248/2012

• FundRef URI

  http://www.fct.pt/apoios/projectos/consulta/vglobal_projecto.phtml.en?idProjecto=124452&idElemConcurso=5819

• Funder

  FCT - Fundação para a Ciência e a Tecnologia, I.P.

• Funder's country

  Portugal

• Funding program

  3599-PPCDT

• Funding amount

  126,556.00 €

• Start date

  2013-06-01

• End date

  2015-11-30